Pediatric oncology has made remarkable strides in treating one of the most prevalent malignancies of childhood -- acute lymphoblastic leukemia (ALL). A diagnosis that was at one time nearly always fatal is now associated with a high probability for long-term disease-free survival. A major contributor to this high rate of success is central nervous system (CNS) treatment to prevent CNS leukemia. CNS treatment presents a difficult dilemma, however. The prognosis for long-term survival following a CNS relapse is poor; yet CNS treatment has been associated with significant compromise of physical and cognitive development. As prospects for long-term disease-free survival improve, therefore, the adverse consequences of treatment are of increasing medical concern. During the initial period of this grant, we determined whether certain children are at greater risk for adverse effects of CNS treatment by virtue of their age and sex. In the proposed continuation, we will determine (1) whether specific treatment agents are differentially toxic depending on dose levels or their use in combination with one another; and (2) whether the effects of treatment are uniform or whether different aspects of development (e.g., growth, cognition) are differentially sensitive to specific treatment agents. A key aim of the research will be to determine whether application of a hyperfractionation schedule to deliver cranial irradiation (XRT) can reduce toxicity without sacrificing efficacy. Two studies are planned, one retrospective and one prospective, in which neurobehavioral development and bone growth will be assessed in these children. Specific treatments to be evaluated will be cranial radiation therapy (delivered in standard fractions or a hyperfractionation schedule) and intravenous methotrexate therapy (standard-dose and high-dose). The data to be generated will be important not only for computing the relative risks and benefits of treatment alternatives, but also for providing any early intervention that may be able to ameliorate possible adverse effects where no equally efficacious but less toxic alternative exists.